Genetic Variant RAD50:p.Ser1257Leu (chr5-132642194-TCA-CTG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_005732.4(RAD50):c.3769_3771delTCAinsCTG (p.Ser1257Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S1257A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 183984); p.S1257L: Uncertain_significance (ClinVar VariationId 1734764, 1 star); p.S1257P: Uncertain_significance (ClinVar VariationId 954365, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

RAD50
NM_005732.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

Publications

0 publications found

Variant links:

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

RAD50 Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome-like disorder
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD50 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

TH2LCRR (HGNC:40495): ()

TH2LCRR links:

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new If you want to explore the variant's impact on the transcript NM_005732.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000198 by highest known P/LP ClinVar AF 0.000198) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
RAD50 NM_005732.4	MANE Select	c.3769_3771delTCAinsCTG p.Ser1257Leu	missense	N/A	Prot: NP_005723.2
TH2LCRR NR_132125.1		n.189+2_189+4delTGAinsCAG	splice_donorsplice_regionintron	Intron 2 of 2	Prot:
TH2LCRR NR_132126.1		n.175-3931_175-3929delTGAinsCAG	intron	Intron 1 of 1	Prot:

RAD50 NM_005732.4

MANE Select

HGVSc / HGVSpc.3769_3771delTCAinsCTGp.Ser1257Leu

Exon rankN/A

missense

Prot: NP_005723.2

TH2LCRR NR_132125.1

HGVSc / HGVSpn.189+2_189+4delTGAinsCAG

Exon rankIntron 2 of 2

splice_donorsplice_regionintron

Prot:

TH2LCRR NR_132126.1

HGVSc / HGVSpn.175-3931_175-3929delTGAinsCAG

Exon rankIntron 1 of 1

intron

Prot:

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
RAD50 ENST00000378823.8	TSL:1MANE Select	c.3769_3771delTCAinsCTG p.Ser1257Leu	missense	N/A	Prot: ENSP00000368100.4 UniProt: Q92878-1
ENSG00000283782 ENST00000638452.2	TSL:5	c.3472_3474delTCAinsCTG p.Ser1158Leu	missense	N/A	Prot: ENSP00000492349.2 UniProt: A0A1W2PQ90
TH2LCRR ENST00000458509.1	TSL:1	n.189+2_189+4delTGAinsCAG	splice_donorsplice_regionintron	Intron 2 of 2	Prot:

RAD50 ENST00000378823.8

TSL:1MANE Select

HGVSc / HGVSpc.3769_3771delTCAinsCTGp.Ser1257Leu

Exon rankN/A

missense

Prot: ENSP00000368100.4UniProt: Q92878-1

ENSG00000283782 ENST00000638452.2

TSL:5

HGVSc / HGVSpc.3472_3474delTCAinsCTGp.Ser1158Leu

Exon rankN/A

missense

Prot: ENSP00000492349.2UniProt: A0A1W2PQ90

TH2LCRR ENST00000458509.1

TSL:1

HGVSc / HGVSpn.189+2_189+4delTGAinsCAG

Exon rankIntron 2 of 2

splice_donorsplice_regionintron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence